Project Summary/Abstract The world has crossed a threshold where people suffering from diseases of overnutrition now outnumber those who suffer from undernutrition. The world obesity epidemic has resulted in an unprecedented diabetes epidemic. In a genetic screen, our laboratory recently identified a gene (Ptpn18) that affects the increase in body fat that results from consumption of a Western (high-fat/high-sucrose) diet. Prior to our studies, a physiological role for PTPN18 in diet-induced obesity had not been described. However, in breast cancer, PTPN18 regulates epithelial growth factor (EGF) signaling by dephosphorylating and repressing human EGF receptor 2 (HER2). Through CRSPR/Cas9 gene editing, our lab derived a knock-in mouse with a single amino acid substitution in Ptpn18; D197A, which abolishes its phosphatase activity. The knock-in mice have a dramatic resistance to diet-induced obesity. Therefore, I hypothesize that Ptpn18 is a critical regulator of weight gain and cell proliferation within adipose tissue. I propose to: 1) Identify the direct physiological substrates of Ptpn18 in adipose tissue, 2) Evaluate the role of PTPN18 in cell proliferation within adipose tissue and adipose tissue inflammation, and 3) Characterize energy expenditure and food intake in Ptpn18D197A mice. The results of the proposed experiments will significantly advance our understanding of the function of Ptpn18 and its link to diet-induced obesity. Through the discovery of direct substrates of Ptpn18, I expect to find a novel pathway for regulation of adipose tissue function and its response to diet. While Ptpn18 is unlikely to be a direct therapeutic target, it is possible that the pathway I discover can be mined for therapeutic targets. The overall theme of research in the Attie lab is the genetics of obesity and type 2 diabetes. Our laboratory uses mouse genetics to identify gene loci that contribute to obesity, type 2 diabetes, and metabolic disorders related to obesity and diabetes; e.g. hepatic steatosis and dyslipidemia. During the time in which I am a postdoctoral fellow, I will be trained in new experimental methods, including mass spectrometry, flow cytometry, and large-scale data analysis. I will also gain new expertise in mouse physiology, while refining those skills and techniques I already possess. Dr. Attie will also guide me in developing a teaching philosophy statement and teaching portfolio, as well as providing guidance in securing independent funding. UW-Madison has an outstanding training environment, dedicated to and supportive of collaborative efforts. I will have the support and training necessary to develop as an independent researcher.